Joint modelling of multivariate longitudinal outcomes and a time-to-event: a nonlinear latent class approach

Abstract : A joint model based on a latent class approach is proposed to explore the association between correlated longitudinal quantitative markers and a time-to-event. A longitudinal latent class model describes latent profiles of evolution of the latent process underlying the correlated markers. The latent process is linked to the markers by nonlinear transformations including parameters to be estimated. A proportional hazard model describes the joint risk of event according to the latent classes and two specifications of the risk function are considered: a parametric function and a semi-parametric function based on splines. Depending on the chosen risk function, estimation is performed by a maximum likelihood or a maximum penalized likelihood approach. A simulation study validates the estimation procedure. As a latent class model relies on the strong assumption that the markers and the time-to-event are independent conditionally on the latent classes, a test of conditional independence is proposed using the residuals conditional on time-to-event. The procedure does not require any posterior classification and can be conducted using standard statistical softwares. The methodology is applied to describe profiles of cognitive decline in the elderly and their associated risk of dementia.